In a germ free mouse there is minimal lymphoid infiltration in the gut. Upon colonization with[unreadable] normal flora there is significant influx and activation of lymphocytes into the gut mucosa and[unreadable] the phenomenon of controlled or physiologic inflammation is established. It is generally[unreadable] recognized that regulatory cells play a key role in the maintenance of this state. A trialogue[unreadable] between bacterial epithelial: T cell interactions has been demonstrated in a variety of different[unreadable] studies. We propose that bacterial:epithelial interactions promote an environment where[unreadable] specific Tregs can be generated. Commensal flora may upregulate/induce the expression of[unreadable] nonclassical class I molecules invovled in the activation of Tregs as well as promote selective[unreadable] chemokine production that recruits Tregs or Treg precursors into the mucosa and epithelium.[unreadable] Within the epithelium bacterial Ags presented by nonclassical class I molecules on lECs can[unreadable] activate Tregs to effect their function: the maintenance of the normal physiologic[unreadable] inflammatory state.[unreadable] In inflammatory bowel disease any number of defects in this process can lead to a failure in[unreadable] regulation. We have already shown that IBD lECs display defective expression of gplSO and[unreadable] CDld. The mechanism(s) underlying these defects have not been defined. Alteration in[unreadable] chemokine or cytokine production may account for these observations. This proposal will test[unreadable] distinct aspects of this model (in health and disease - all in human tissues).[unreadable] Specific Aim #1. Determine which Tregs are present (or absent) in the normal and IBD[unreadable] intestine and correlate these with defects in non-classical class I molecule expression in IBD[unreadable] (aim #2). Is the defect in TrE cells in IBD tissues reflective of a selective or global defect in[unreadable] Tregs?[unreadable] Specific Aim #2: Determine the expression and regulation of non-classical class I molecules[unreadable] on intestinal epithelial cells and define defects in expression on IBD lECs.